New approaches to study tumor microvesicles

点击翻译按钮获取中文摘要

ABSTRACT Tumor-derived microvesicles (TMVs), a vesicle subtype in the family of extracellular vesicles (EVs), contain bioactive protein and nucleic acid cargoes and have emerged as important mediators of intercellular communication in the tumor microenvironment (TME). By virtue of their roles in the TME, EVs have been thought to support the spread of metastatic disease by promoting tumor expansion and tumor invasive activity, dampening immune responses, and facilitating angiogenesis. Thus, identifying and targeting molecules and signaling pathways that control EV biogenesis and/or function has the potential to lead to novel and complementary therapeutic strategies. Moreover, the discovery that EVs are found in circulation has heightened interest in these vesicles as promising diagnostic and prognostic platforms. Although we have learned a great deal about EV function over the past decade, there is need to learn much more about how the various EV subtypes are formed and how they engage and affect recipient cells in the TME. In particular, there is a critical need to define the cellular pathways and signaling mechanisms that underlie TMV biogenesis to better understand their paracrine properties and function. Relative to tumor exosomes, the other prominent EV subtype shed by tumor cells, we know significantly less about TMVs. Our understanding of the molecular principles that control TMV formation and cargo incorporation remains limited in large part due to limitations in isolating and precisely defining the molecular makeup of individual EV populations. To begin to explore the molecular mechanisms of TMV formation and release, we have adapted a biochemical screen for TMV proteomic studies aimed at identifying TMV- specific cargo and testing novel regulation of TMV biogenesis. The findings that result from this pilot study will form the basis of delineating and testing a mechanistic framework underlying TMV biogenesis and function in preclinical models of tumor progression. Given our experience and expertise, our laboratory is well position to carry out these investigations.